Bidirectional Pathological Axis Between Alzheimer's Disease and Circadian Rhythm Disturbance: Mechanisms and Therapeutic Strategies

ABSTRACT

Circadian rhythm disturbance is highly prevalent in patients with Alzheimer's disease (AD) and is consistently associated with more rapid cognitive decline and reduced quality of life. Accumulating evidence supports a bidirectional relationship between circadian rhythm disruption and AD pathology, in which each may reciprocally exacerbate the other. However, whether circadian rhythm disturbance acts as an independent causal driver of AD initiation or primarily as a factor that modifies and accelerates pathology once it is underway remains an open question. This article synthesizes current evidence on the proposed mechanisms linking circadian dysregulation to AD pathophysiology, with particular attention to the suprachiasmatic nucleus (SCN), glymphatic clearance, clock gene networks, and apolipoprotein E ε4 allele (APOE ε4) genotype. Emerging circadian‐targeted interventions, including both pharmacological and nonpharmacological approaches, are also reviewed and their current limitations are discussed. A more complete understanding of this bidirectional axis may help inform future research directions and ultimately contribute to the development of early monitoring and combination treatment strategies for AD.